Cured biodegradable microparticles and scaffolds and methods of making and using the same

ABSTRACT

A method of forming cured microparticles includes providing a poly(glycerol sebacate) resin in an uncured state. The method also includes forming the composition into a plurality of uncured microparticles and curing the uncured microparticles to form the plurality of cured microparticles. The uncured microparticles are free of a photo-induced crosslinker. A method of forming a scaffold includes providing microparticles including poly(glycerol sebacate) in a three-dimensional arrangement. The method also includes stimulating the microparticles in the three-dimensional arrangement to sinter the microparticles, thereby forming the scaffold having a plurality of pores. A scaffold is formed of a plurality of microparticles including a poly(glycerol sebacate) thermoset resin in a three-dimensional arrangement. The scaffold has a plurality of pores.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalApplication No. 62/479,661 filed Mar. 31, 2017, and U.S. ProvisionalApplication No. 62/547,559 filed Aug. 18, 2017, both of which are herebyincorporated by reference in their entirety herein.

FIELD OF THE INVENTION

The present disclosure is generally directed to cured configurations ofbiodegradable polymeric elastomers.

BACKGROUND OF THE INVENTION

Poly(glycerol sebacate) (PGS) is a cross-linkable elastomer formed as aco-polymer from glycerol and sebacic acid. PGS is biocompatible andbiodegradable, reduces inflammation, improves healing, and hasantimicrobial properties, all of which make it useful as a biomaterialin the biomedical field.

To create a PGS thermoset/solid structure, neat PGS resin must becrosslinked/cured at elevated temperatures. However, at physiologicaltemperatures, PGS resin is a liquid and flows, thus limiting theapplication of neat PGS resin. Therefore, it is generally required tocast the PGS resin in a mold to hold the PGS resin shape during thecrosslinking step at an elevated temperature to create a shapedthermoset structure.

As a result, creating any kind of spherical conformations of PGS isespecially difficult, even more so when microparticles or microspheresare the intended article. PGS microparticles may be created from neatPGS resin through emulsion and solvent evaporation, but subsequentthermal processing steps to cure the PGS microparticles result inmelting the PGS microparticles and a loss of their sphericalconformation.

Other methods of making crosslinked PGS structures involve the use of adissolvable solid form, addition of fillers to “solidify” the resin, orchanging the chemistry of PGS to allow for crosslinking methods otherthan thermal curing.

U.S. Pub. No. 2009/0011486 describes nano/microparticles formed frompoly(glycerol sebacate acrylate) (PGSA). However, this involvesincorporating photo-crosslinkers into PGSA and ultraviolet (UV)-curingthe PGSA microparticles to form solid particles. UV photoinitiators andcatalytic crosslink agents are known to elicit immune responses to boththe toxicity and by-products of use, making such particles unfavorablefor use in biological systems.

BRIEF DESCRIPTION OF THE INVENTION

What is needed is a method of particalizing PGS resin compositions andmaking microparticles containing PGS in a spherical conformation thatcan be performed without the need to use forms, thermoset fillers, orthe introduction of photo-induced crosslinkers or other initiators whichmay be harmful in biological systems.

Lactide and glycolide microparticles are difficult to formulate and arehard and rigid limiting their use while elastomers are notoriouslydifficult to process into shapes without a mold. Embodiments of presentinvention allow for mold-free formation of an elastomeric particle thatextends or provides certain properties that rigid polymers cannotprovide like deformation and compressibility.

PGS microparticles can be used in the development of elastomeric,surface eroding microparticles with tunable degradation kinetics for afinal article of manufacture. The PGS microparticles can be designedaccording to stoichiometry of starting materials, degree of crosslink orparticle formation method (e.g. encapsulation, micellular, emulsion).

In an embodiment, a method of forming a plurality of curedmicroparticles includes providing a composition comprising apoly(glycerol sebacate) resin in an uncured state and forming thecomposition into a plurality of uncured microparticles, the plurality ofuncured microparticles being free of a photo-induced crosslinker, andcuring the plurality of uncured microparticles to form the plurality ofcured microparticles.

In some embodiments, the step of forming includes combining the PGSresin composition with a phase-incompatible liquid. In some embodimentsthe phase-incompatible liquid is an oil; in some embodiments thephase-incompatible liquid is an elastomer; in some embodiments, thephase-incompatible liquid is capable of undergoing a reversible sol-geltransition.

In another embodiment, a method of forming a scaffold includes providinga plurality of microparticles comprising poly(glycerol sebacate) in athree-dimensional arrangement and stimulating the plurality ofmicroparticles to sinter them into the scaffold.

In yet another embodiment, a scaffold is formed of a plurality ofmicroparticles comprising a poly(glycerol sebacate) thermoset resin in athree-dimensional arrangement, the scaffold having a plurality of pores.

Various features and advantages of the present invention will beapparent from the following more detailed description, taken inconjunction with the accompanying drawings which illustrate, by way ofexample, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an image of different sizes of cured PGS particles inembodiments of the present disclosure.

FIG. 2 is an image of a cluster of cured PGS microparticles in anembodiment of the present disclosure.

FIG. 3 is an image of different shapes of cured PGS particles inembodiments of the present disclosure.

FIG. 4 is an image of PGS microspheres in an embodiment of the presentdisclosure.

FIG. 5 schematically shows a process for forming microparticles in avertical column in an embodiment of the present disclosure.

FIG. 6 schematically shows a process for forming PGS microparticles withalginate as an emulsifier in an embodiment of the present disclosure.

FIG. 7 is an image of PGS microspheres formed by the process of FIG. 6.

FIG. 8 is a schematic capsule of microparticles with interspheroid voidspaces in an embodiment of the present disclosure.

FIG. 9A is a laser-directed infrared (LDIR) image of a 25:75elastomer:ester pressure-sensitive adhesive system.

FIG. 9B is an LDIR image of a 50:50 elastomer:ester pressure-sensitiveadhesive system.

FIG. 9C is an LDIR image of a 75:25 elastomer:ester pressure-sensitiveadhesive system.

FIG. 10A is an image of a hollow sphere of molded and cured PGS flourparticles in an embodiment of the present disclosure.

FIG. 10B is an image showing the hollow core of half of the hollowsphere of FIG. 10A after breaking apart the hollow sphere of FIG. 10A.

FIG. 10C is an image of another view of the half of the hollow sphere ofFIG. 10B.

FIG. 11 is an image of a portion of the surface of the hollow sphere ofFIG. 10A after microwaving the PGS flour particles.

FIG. 12 schematically shows a mini-implantable bioreactor.

FIG. 13 is FTIR spectra of PGS microspheres loaded with curcumin by anemulsification process similar that of FIG. 6.

FIG. 14 shows PGS microspheres containing curcumin.

Wherever possible, the same reference numbers will be used throughoutthe drawings to represent the same parts.

DETAILED DESCRIPTION OF THE INVENTION

Provided are cured biodegradable particles, scaffolds, methods of makingand using cured biodegradable particles and scaffolds as well ascompositions containing cured biodegradable particles.

Exemplary embodiments provide convertible microparticles that aresupported without a mold during transition from an uncured to curedstate.

Embodiments of the present disclosure, for example, in comparison toconcepts failing to include one or more of the features disclosedherein, provide spherical poly(ol)-diacid co-polymer particles withoutthe use of a mold, provide spherical PGS particles without the use of amold, provide spherical PGS microparticles, provide spherical PGSnanoparticles, provide PGS microparticles free of photoinitiator,provide PGS microparticles consisting of PGS polymer, provide PGSmicroparticles free of any chemical component that would react with thePGS polymer during curing, provide three-dimensional (3-D) scaffoldsfrom PGS microparticles, provide drug-loaded PGS microparticles, providedrug-coated PGS microparticles, provide cured microparticles free ofphotoinitiator, provide cured microparticles free of additives, providemicroparticles free of photo-induced crosslinkers, permit visualizationof the surface chemical structure of a pressure-sensitive adhesive,promote incorporation of an active pharmaceutical ingredient (API) intocompositions for controlled release of the API, or combinations thereof.

As used herein, the term “microparticle” refers to a particle having alargest dimension between 1 micrometer (μm) and 1000 μm. The termencompasses a plurality of geometric shapes. Thus, microparticles may beeither regular or irregular or of a geometrically distinct shape, suchas, for example, spherical or rough. In some presently preferredembodiments, the microparticles are spherical.

As used herein, the term “nanoparticle” refers to a particle having alargest dimension between 1 nanometer (nm) and 1000 nm.

The present disclosure relates to processes of making microparticles andmodulated porous microparticle-based cell scaffold technologiesincluding poly(glycerol sebacate) (PGS), PGS microparticles formed fromsuch processes including flour composites, processes for the formationof scaffolds comprised of PGS microparticles, PGS scaffolds formed fromsuch processes, and the use of these PGS microparticles and/or scaffoldsfor cell and drug delivery applications. These PGS microparticles and/orscaffolds may also be used for cell culture and generation of newtissues.

The present disclosure also relates to the in-situ formation ofcompositions containing microspherical micro-domains, which may beuseful, for example, in creating pressure-sensitive adhesives (PSAs) orother compositions with micro-domains loaded with an activepharmaceutical ingredient.

In some embodiments, processes form particles that include PGS. In someembodiments, processes form a 3-D scaffold from particles that includePGS.

In exemplary embodiments, thermoset microparticles are formed withoutmold casting. Through combinations of microparticle forming technologiesand PGS curing technologies, distinct microparticles and 3-dimensionalscaffolds formed from microparticles are created.

In exemplary embodiments, uncured microparticles are dispersed andsupported in a continuous phase matrix, typically via suspension.Appropriate energy is applied to the uncured microparticles while theyare suspended in the continuous phase matrix to form cured, thermosetsubstantially spherical microparticles. In some embodiments the energyis heat, electromagnetic radiation (e.g. IR and/or microwave energy) ora combination thereof.

The continuous phase matrix may be any composition that isphase-incompatible with the uncured microparticles and in which theuncured microparticles are supported in their shape until cured. Thesuspension may occur by any appropriate mechanism, including, but notlimited to, shear mixing, induced flow, sonication, or control oradjustment of the specific gravity of the dispersed phase or thecontinuous phase. When the applied energy is microwave energy, thecontinuous phase matrix is preferably selected to be transparent tomicrowaves.

In some embodiments, PGS microparticles and scaffolds are cured throughmicrowaving or other long wavelength electromagnetic radiation, such asIR. PGS has significant sensitivity to microwave energy. This energy mayalso be used to further sinter/anneal formed microparticles of PGS inproximity to each other. This tunable process may be modified throughselective shapes and molds, selective energy processing with microwavedopants, pre-conditioning of irregular shape-to-sphere phase exclusionremodeling, and pre-loading with cells or drugs prior to microwaving.

It will be appreciated however, that PGS microparticles may also becured by heating, including through conductive and/or convectiveheating. The heating may be carried out alone or in combination withmicrowave curing

Although methods and compositions are described herein primarily withrespect to PGS formed solely from glycerol and sebacic acid, polymericmicroparticles from co-polymers of glycerol, sebacic acid, and a thirdmonomer or from non-PGS polymers or co-polymers may also be formed byand used in the present compositions and methods. In some embodiments, aPGS polymer is a co-polymer of glycerol, sebacic acid, and an acrylate,referred to as poly(glycerol sebacate acrylate) (PGSA). In otherembodiments, a PGS polymer is a co-polymer of glycerol, sebacic acid,and a urethane, referred to as poly(glycerol sebacate urethane) (PGSU).If non-PGS polymers are used, those that require elevated temperaturesfor crosslinking/curing may be preferred.

In some embodiments, the polymer formed into a polymeric microparticleis an ester co-polymer formed from any combination of a poly(ol) and anacid. Appropriate acid monomers may include compounds having one or moreacid substituents, including, but not limited to, monoacids, diacids,triacids, tetraacids, and the like. In some embodiments, the acidmonomer is a diacid. Such diacids may have the formula[HOOC(CH₂)_(n)COOH], where n=1-30. In exemplary embodiments, the diacidincludes malonic acid, succinic acid, glutaric acid, adipic acid,pimelic acid, suberic acid, azelaic acid, sebacic acid, or combinationsthereof.

Additionally, various non-PGS polymeric compositions may be used incombination with PGS, which may include, but are not limited to, naturalpolymers, synthetic polymers, or co-polymers of PGS and non-PGSmonomers. Microparticles may be formed from such compositions.

Particle Formation

Different methods of microparticle forming technology, which mayinclude, but are not limited to, emulsions, phase-separation, spraydrying/congealing, spinning disk atomization, wax coating and hot melt,and freeze drying, may be utilized to form PGS microparticles orcore-shell PGS microparticles prior to curing in a continuous matrixphase.

Depending on the materials and conditions, microparticles having a rangeof physical and chemical properties may be obtained. In someembodiments, the particles are nanoparticle having an average size ofless than 1 μm. The PGS may be synthesized with a range of molar ratiosof glycerol to sebacic acid, resulting in microparticles having a rangeof hydrophilicities. In some embodiments, cell culture nutrients areincorporated into the PGS during PGS synthesis, during PGS microparticleformation, or post-loading to improve cell culture capabilities. In someembodiments, oxygen-producing species, such as, for example, magnesiumdioxide, may be incorporated into the PGS during PGS synthesis, duringPGS microparticle formation, or post-loading to improve oxygenation ofculture cells, particularly in dense cell clusters.

Exemplary embodiments can provide for microparticles of PGS or otherbiodegradable polymers to be created and cured into an elastomer in onecontinuous step, allowing for the formation of microparticles thatretain their spherical shape during thermal curing at elevatedtemperatures and/or microwave curing.

In some embodiments, concepts of microparticle formation and thermalcuring of PGS are utilized and combined into a single step to formcrosslinked PGS microparticles. In an exemplary embodiment, the processof making PGS microparticles occurs in a single vessel.

Methods in accordance with exemplary embodiments thus permit easyscale-up of microparticle formation as well as consistent crosslinkingdensities for all PGS microparticles.

In some embodiments, methods create neat, crosslinked, substantiallyspherical PGS microparticles (i.e. 100% poly(glycerol sebacate) with noadditives) that do not melt at elevated temperatures.

Methods of making PGS particles may be tuned to create microparticles10, nanoparticles, or larger particles 20, as well as PGS strands 30 andother round configurations of cured PGS, as shown in FIG. 1, FIG. 2,FIG. 3, and FIG. 4. The particle size may be tuned, for example, byadjusting the intensity of shear mixing by adjusting the number ofrevolutions per minute (RPM), the impeller size and/or shape, and/or thesize and shape of the reaction vessel, by adjusting the continuousphase:dispersed phase ratio, by adjusting the viscosity of thecontinuous phase, by adjusting the viscosity of the dispersed phase,and/or by the absence or presence and amount of emulsifiers and/orstabilizers.

Referring to FIG. 1, the mass of microparticles 10 and the mass oflarger particles 20 were formed under similar conditions, with theprimary difference being a smaller stir bar producing the largerparticles 20. FIG. 2 shows microparticles formed in the presence ofmonolaurin as a stabilizer. FIG. 3 and FIG. 4 show variations toparticle size and shape based on variations to the cure rate and thestir bar.

Methods in accordance with exemplary embodiments have an additionaladvantage of being able to form microparticles of a narrow particle sizedistribution.

In some embodiments, the composition of the microparticle includes a PGSresin having a weight average molecular weight in the range of fromabout 5,000 to about 50,000 Da. In some such embodiments, the resin hasa weight average molecular weight in the range of from about 15,000 toabout 25,000 Da.

In some embodiments, the microparticle introduced as the dispersed phaseis pure resin and in other embodiments a mixture including a PGS resinand a micronized thermoset filler including PGS (sometimes also referredto herein as “flour”). In some such embodiments, the thermoset fillerand the resin each have a molar ratio of glycerol to sebacic acid in therange of 0.7:1 to 1.3:1. In some such embodiments, the thermoset fillerhas a particle size between 0.5 and 1000 μm. In some such embodiments,the thermoset filler has a particle size less than 250 μm. In some suchembodiments, the thermoset filler is present in an amount in the rangeof from about 10% by weight to about 90% by weight of the mixture. Insome such embodiments, the thermoset filler is present in an amount inthe range of from about 40% by weight to about 70% by weight of themixture.

In some embodiments, PGS microparticles are formed through shear mixing.While shear mixing is a technique to make microparticles throughemulsions, exemplary embodiments maintain the microparticleconfiguration during shear mixing while thermally curing themicroparticles at the same time to form solid, crosslinked,spheroid-shaped PGS microparticles. A spheroid shape is considered tohave the least surface area per unit volume and lowest surface energy ofa particle in a medium.

Microparticles having a diameter in the range of 1 μm to 1 mm may beformed. In some embodiments, the microparticles have a particle size inthe range of 50 μm to 300 μm, alternatively in the range of 100 μm to500 μm, or any value, range, or sub-range therebetween. The size of theparticles may be tuned via the amount of shear mixing as well as thevolume ratio of PGS-to-matrix.

In some embodiments, neat PGS microparticles are manufactured byproviding a liquid that is phase-incompatible with PGS. Thephase-incompatible liquid may be any liquid or viscous medium that isphase-incompatible with the PGS. In some embodiments, thephase-incompatible liquid is non-reactive with the PGS, such as, forexample, a mineral oil or a mixture of higher alkanes and/orcycloalkanes. In other embodiments, the phase-incompatible liquidincludes one or more compounds that are reactive with the PGS, such as,for example, natural oils, which may include, but are not limited to,olive oil, safflower oil, sunflower oil, canola oil, or combinationsthereof. In some embodiments, the phase-incompatible liquid is stirredand heated, such as, for example, to 130° C. (266° F.) for mineral oil,in a reactor vessel that holds vacuum. In still other embodiments, thephase-incompatible liquid may be a base that can be used in forming anin-situ composition, for example an isobutylene or acrylic base forforming an adhesive composition. It will be appreciated that heating isnot required and that in some embodiments the processes described hereinmay be carried out with the phase-incompatible liquid at roomtemperature.

A vacuum, such as, for example, 10 torr, is applied to thephase-incompatible liquid to remove dissolved gases prior to addition ofPGS resin. The vacuum is removed and molten PGS is slowly and directlyadded to the phase-incompatible liquid, optionally under stirring. Thismay be accomplished by delivery through a needle, such as shown in FIG.5, for microparticle formation.

After the PGS resin has been added, the 10-torr vacuum is reapplied andthe PGS microparticles are cured, which in one embodiment is achieved byheating in which the mineral oil or other phase incompatible liquid iskept at 130° C. (266° F.) and under stirring to crosslink the PGS. After24 hours, heating, vacuum, and stirring are removed. The PGSmicroparticles are then filtered and washed.

In some embodiments, methods take advantage of specific gravity andbuoyancy in a vertical column, such as the one shown in FIG. 5. Aphase-incompatible liquid 51 of higher specific gravity than PGS fills avessel, shown here as a vertical column 52. A tubular delivery fixture53 at the bottom of the column permits introduction of the PGS resin 54from a reservoir 55, in the form of a hypodermic needle inserted intothe liquid in FIG. 5. The vertical column 52 and reservoir 55 areoptionally heated to allow flow.

As illustrated in FIG. 5, the vertical column 52 is surrounded with anappropriate radiation source 56, such as, for example, infrared (IR) ormicrowave, that is configured to deliver energy through the verticalcolumn 52, the phase-incompatible liquid 51, and the PGS resin 54, withor without heating of the phase-incompatible liquid 51. In embodimentsin which a radiation source, particularly microwave, is employed, thephase-incompatible liquid 51 is also selected to avoid dipolarinteraction with electromagnetic radiation.

Increasing the needle bore size increases the sphere volume of the PGSresin particles. The lower specific gravity of the uncured PGS resin 54causes the particles to rise in the vertical column 52. Theelectromagnetic radiation source 56 cures these particle on the rise. Areversal of the specific gravity ratio may be used to change thedirection of the PGS movement. In some embodiments, the system isconfigured as bleed and feed 57. Exemplary embodiments deliver themolten PGS resin 54 to the hot mineral oil through a needle at aconstant rate to create more uniform particle sizes. Createdmicrocylinders of a specific aspect ratio may also be introduced to thevertical column 52 to remodel from cylinder to sphere.

In some embodiments, the average particle size is adjusted by selectionof the gauge of the syringe needle forming the resin droplets. In otherembodiments, an ultrasonic droplet sonicator may be used in combinationwith or in lieu of a syringe needle. The average particle size of thePGS resin 54 introduced into the column 52 is adjusted by the sonicatorfrequency when forming the resin droplets. Increasing the frequency ofthe sonication decreases the average particle size. It will beappreciated that the vessel does not have to be a column 52 and that thePGS resin can be introduced into the phase-incompatible liquid from thetop or bottom of the vessel.

Thus, PGS microparticles having a size of less than 1 millimeter (mm)are formed without the use of a mold, the particles being formed andthen cured while suspended in the phase-incompatible liquid of thecolumn 52.

Additives may be included in the continuous phase to form finerparticles, to form larger particles, to form a more monodispersedistribution of particle sizes, to help prevent coalescence orflocculation of particles, or a combination thereof. Additives mayinclude, but are not limited to, surfactants, emulsifiers, thickeningagents, stabilizers, suspending agents, fatty acids, monoglycerides,triglycerides, polymeric stabilizers, polyethylene glycol (PEG),polycaprolactone (PCL), PEG dimethyl ether, sorbitan esters,polysorbates, polysaccharides, quaternary amines, sodium dodecyl sulfate(SDS), metal oxides, solid nanoparticle stabilizers, naturalemulsifiers, lanolin, arabic gum, gelatin, lecithin, or combinationsthereof.

The additives may be reactive or non-reactive with the PGS. Additivesmay be provided in the dispersed phase or the continuous phase. That is,in some embodiments the additives may be mixed into the PGS resin priorto forming the dispersed phase while in other embodiments, additives canbe incorporated into the continuous phase to provide a surface coatingsubstantially at or near the surface of the microparticles.

In still other embodiments, the continuous phase can be used as areversible matrix for the formation of PGS microspheres. PGSmicrospheres can be formed through known methods as described above. Themicrospheres are dispersed into a phase-incompatible liquid (continuousphase) that can undergo sol-gel transitions. The continuous phase isthen solidified through this sol-gel transition, thus locking theparticles into their shape configuration. PGS can then be cured (throughheating or microwave) while maintaining their shape. Following cure, thecontinuous phase is then liquified through the sol-gel transition tofree the PGS microparticles.

In certain embodiments, this concept is used to form core-shellmicroparticles where the core is a phase-incompatible liquid that canundergo sol-gel transitions, and the shell is PGS resin. Thesecore-shell microparticles can be formed through double emulsionprocesses.

Factors influencing sol-gel transitions include changes in temperature,pH, and non-covalent interactions, such as ionic, hydrogen-bonding, Vander Waals forces. Materials that can be used for the sol-gel transitionsinclude temperature-responsive polymers such as gelatin, poly(NIPAM),and hydroxypropyl cellulose; ionic-responsive polymers such as alginateand chitosan; light-responsive polymers; and various self-assemblyand/or supramolecular polymers. a core-shell microparticle is formedfrom a composition of two phase-incompatible liquids, with one beingmore energetically favorable to the continuous phase, such as, forexample, a PGS-gelatin system.

A method of making PGS microparticles can be achieved through a doubleemulsion that includes mixing a solution of PGS into an aqueous basedstabilizer, such as water and PVA, for example, to create an initialemulsion. The method further includes mixing the initial emulsion into aliquid that is phase-incompatible with PGS, PVA, and water to create asecond emulsion.

The phase-incompatible liquid may be stirred at room temperature at thetime of mixing; the method further includes heating the mineral oil togreater than 100° C. (212° F.) to drive off solvent, especially water,thereby forming a core-shell microparticle. The method further includesapplying a vacuum or reduced pressure and heat in the range of 100° C.to 150° C. (212° F. to 302° F.) to the core-shell microparticles tocrosslink the PGS. After about 24 hours, heating, vacuum, and stirringare removed, and the PVA-PGS microparticles are filtered and washed toremove residual oil. The resulting PVA-PGS microparticles can be washedwith water to remove the PVA shell, leaving the cured PGSmicroparticles.

Liquids other than mineral oil may be used as the continuous phase foran emulsion, provided that they are phase-incompatible with PGS andwater and are thermally stable at temperatures in the range of 100° C.to 150° C. (212° F. to 302° F.). In some embodiments, temperatures of upto 300° C. (572° F.) may be used to crosslink the microparticles,provided that the continuous phase liquid is thermally stable at thosetemperatures.

In another embodiment, alginate is used as an emulsifying agent forformation of PGS microspheres. FIG. 6 shows an exemplary process. PGSresin in the range of 10 wt % in a solvent up to neat (i.e. 100% wt) PGSresin is added dropwise to an aqueous alginate solution 61. The amountof alginate in the aqueous alginate solution 61 may be any amount thatcan be solubilized in the aqueous solution, such as, for example, in therange of 0.5 to 4 wt % alginate. Any solvent that solubilizes PGS may beused, including, but not limited to, isopropyl alcohol, ethyl acetate,or tetrahydrofuran. The solvent may be stirred or stagnant at the timeof addition.

The addition forms a PGS-alginate-containing solution 62 of initialuncured PGS microspheres. This PGS-alginate-containing solution 62 isadded dropwise or continuously to a divalent cation salt solution torapidly ionically gel the alginate into spheres and form aPGS-alginate-gel-containing solution 63. Appropriate divalent cationsalts may include, but are not limited to, calcium chloride (CaCl₂),barium chloride (BaCl₂), magnesium chloride (MgCl₂), strontium chloride(SrCl₂), cobalt (II) chloride (CoCl₂), cupric chloride (CuCl₂), or zincchloride (ZnCl₂). Salts are washed out by multiple rinses of thePGS-alginate spheres using deionized water. The deionized water is thenremoved, leaving hydrated PGS-alginate spheres.

The hydrated PGS-alginate spheres are then frozen to form frozenPGS-alginate spheres 64. The frozen PGS-alginate spheres 64 are thenlyophilized to form dry PGS-alginate spheres 65. The dried PGS-alginatespheres 65 are then cured to crosslink the PGS microspheres formingcured, alginate-entrapped PGS microspheres 66. Appropriate curingprocesses may include, but are not limited to, microwaving, heating inan oil, or heating in a vacuum oven. The cured, alginate-entrapped PGSmicrospheres 66 are placed into an alginate-chelating solution, whichmay be stirred or stagnant at the time of addition, to chelate thedivalent cation away from alginate. This reverses the alginatecrosslinking, which allows the alginate to degrade, releasing the curedPGS microparticles from the alginate to form a cured PGSmicroparticle-containing solution 67. Appropriate alginate chelators inthe alginate-chelating solution may include, but are not limited to,sodium citrate, 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid(BAPTA), ethylene glycol-bis((3-aminoethyl ether)-N,N,N′,N′-tetraaceticacid, (EGTA), and/or ethylenediaminetetraacetic acid (EDTA).Alternatively, an enzyme, such as, for example, alginate lyase may beused to degrade the alginate and release the cured PGS microparticles.The cured PGS microparticles are then concentrated, such as, forexample, by centrifugation, and washed multiple times to remove residualdegraded alginate and sodium citrate salts prior to drying and storageof the final PGS microparticles 68. FIG. 7 shows microspheres made bysuch a process.

The average particle size and range of the PGS microparticles may betuned by adjusting one or more parameters of the process, which mayinclude, but are not limited to, the weight percentage of the alginate,the stirring speed (shear rate), the weight percentage of PGS, the useof a surfactant, and the solvent (or lack thereof) used with PGS resin.

In some embodiments, the continuous matrix phase for formation of curedmicrospheres is a base for in-situ formation of a composition containingsuspended cured microspheres. For example, in some embodiments thecontinuous matrix phase is an elastomer. The elastomer may be a polymerused with PGS to form a PSA. In some embodiments, the elastomer isacrylic-based. In other embodiments, the elastomer is isobutylene-based.The uncured dispersed microspherical micro-domains of PGS may be curedby microwave or conductive heating to form cured microspheres. Thephase-incompatible material for the base material for the continuousphase may be selected to be substantially invisible to microwave (i.e.having little or no dipole moment), the continuous phase resists curingsuch that the resulting composition can still exhibit some viscous floweven after the dispersed microparticles have cured.

The use of PGS as spherical microdomains within a base composition maybe used in formulations for bioresorbable controlled release of activesand biologics delivered to the skin. In microstructures where the PGSdomains acts like a particle, the controlled release structural domainas well as a component to a pressure-sensitive adhesive (PSA) may mean adifferent approach to formulating an active PSA, rather than consideringthe component merely as a service component to a wound care PSAadhesive. In some embodiments, PGS micro-domains contain APIs for woundcare in a controlled release construct and contribute to adhesion of aPSA.

PGS has inherent antimicrobial and non-immunogenic features in tissueengineering. Patients suffering from chronic wounds, like diabeticulcers, have compromised immune systems and often have an allergicreaction to PSAs commonly found in wound care dressings, which mayfurther damage the fragile skin of older patients leading to infectionand other complications.

When PGS is blended with an elastomer of a typical transdermal materialto form a PSA, the PGS forms microspherical structures in an elastomermatrix under certain conditions. The PGS functionally contributes to thephysical tack but may be independently formulated with an API or othercontrolled release agents before it is formulated into the elastomer. Insuch cases, these microspheres may act to provide controlled release,while still contributing to the physical tack of the PSA. In chronicwounds, for example, an antibiotic or trophic agent may be provided asthe controlled release agent to improve healing from the perimeter of awound. The PGS or the PSA composition may serve as another constructconcept for transdermal drug delivery. Essentially the development ofthe microsphere simultaneously results in the PGS microsphere acting asboth as a functional PSA component and a delivery vehicle.

In some embodiments, a method of forming a pressure-sensitive adhesivecomposition includes combining a polymeric ester with one or morecontrolled release agents to form an ester phase. The combining loadsthe polymeric ester with the controlled release agent. The methodfurther includes combining the ester phase with an elastomer phaseincluding an elastomeric polymer. The ester phase and the elastomerphase are combined at a ratio which produces a discontinuousmicrospherical ester phase in a continuous elastomeric phase matrix toform a pressure-sensitive adhesive composition. In some embodiments, theester includes PGS. In some embodiments, the elastomer includespolyisobutylene (PIB). In some embodiments, the elastomer includes anacrylic.

Controlled release agents for PSAs may include, but are not limited to,wound care agents, nutritional doping/bioactive agents, API agents,biologic agents, drug agents, gene transfer technology agents,co-polymer particle development agents, or island agents in the seamatrix dissolution. Wound care agents may include, but are not limitedto, trophic agents, hemostatic agents, antibiotics, antimicrobials,analgesics, APIs, ointments, alginates, hydrogels, fillers, deodorants,Manuka honey, growth enhancers, or stimulants.

In some embodiments, a method includes applying a pressure-sensitiveadhesive composition to a substrate to form a pressure-sensitiveadhesive device. In some embodiments, the pressure-sensitive adhesivedevice is a wound care dressing. In some embodiments, a method includesapplying a pressure-sensitive adhesive device to a target surface. Thepressure-sensitive adhesion composition has sufficient tack to adherethe pressure-sensitive adhesive device to the target surface. Thecontrolled release agents are predominantly associated with themicrospherical ester phase of the pressure-sensitive adhesivecomposition and are released at the target surface over time in acontrolled manner from the pressure-sensitive composition.

Although methods and compositions are described herein primarily withrespect to PGS as the ester component in an ester:elastomer PSA, non-PGSesters may alternatively serve as an ester component in a PSA formed bythe present methods. In some embodiments, the ester component isbiodegradable. In some embodiments, the ester is a co-polymer formedfrom any combination of a poly(ol) and a diacid.

As previously mentioned, some embodiments include a micronized thermosetPGS filler mixed into the PGS resin used to form the microparticleswhile in other embodiments, previously formed filler particles, whichmay be of irregular shape, may be remodeled into spherical form.

The crosslink density of the filler may be as low as 0.00 mol/L up toabout 0.07 mol/L or greater. The crosslink density is calculated withrespect to the thermoset material prior to particularization by soakingsamples in tetrahydrofuran for 24 hours to obtain a swollen mass, drieduntil a constant dry mass is acquired (typically about 3 days) and theswelling percentage is then used to calculate the crosslink densityusing the Flory-Rehner expression for tetra-functional affine networks.A lower crosslink density, which may be as low as 0.00 mol/L, indicatingno or minimal crosslinking, allows for “sintering” or annealing whencuring/microwaving the flour particles.

According to such embodiments, sprayable formulations include a mixtureof PGS including a resin of glycerol-sebacic acid ester, and thermosetPGS that has been processed into a flour or powder of fine particlesize. Mixtures of PGS resin and micronized thermoset PGS are describedin U.S. Pub. No. 2017/0246316 and U.S. Pub. No. 2018/0050128, both ofwhich are hereby incorporated by reference.

In some embodiments, cast and partially-cured PGS thermosets arecryo-milled to form PGS flour. The PGS thermosets particles arepartially cured with enough sol fractions to permit remodeling. PGSflour is a micronized polymer of PGS forming a powder or “flour”consistency. This PGS flour is composed of non-spherical,irregular-shaped microparticles that are generally less than 1000 μm insize. The PGS thermoset may then be further cured to different degreesof crosslinking, thus resulting in PGS flour with varying amounts ofthermoplastic sol fraction. PGS flour with sufficient amounts ofthermoplastic fraction may then be remodeled, by melting of the solfraction, to make PGS microparticles with rounded edges through curingtechniques for PGS, such as, for example, microwaving and/or high heatand vacuum.

In some embodiments, PGS flour particles are modified for a differentparticle size distribution or geometric shape variation or loaded orcoated with one or more controlled release agents, which may include,but are not limited to, nutritional doping/bioactive agents, API agents,biologic agents, drug agents, gene transfer technology agents,co-polymer particle development agents, or island agents in the seamatrix dissolution. Any appropriate loading of controlled release agentsmay be used, such as, for example, up to 60 wt % or up to 70 wt %. Insome embodiments, the controlled release agent does not react with thePGS polymer during curing.

Depending on the crosslinking extent of PGS flour particles, they may beremodeled into microparticles with a more rounded or sphericalconfiguration, including methods, such as, for example, phase exclusionparticle remodeling in a phase-incompatible liquid or microwaveremodeling in a non-dipole liquid or solid.

In some embodiments, a method includes making 100% solids powder coatingfilms using PGS flour and sintering/annealing particles with microwaveor IR energy to encourage sintering/annealing and flow and leveling. PGSparticles that have been crosslinked for less than 48 hours at 120° C.(248° F.) and 10 torr have sufficient lower molecular weightthermoplastic PGS fractions for remodeling. The method includes particlesintering/annealing with coherent and/or non-coherent radiant energyand/or with superheating in a liquid or non-oxidizable gas-plasma.

In some embodiments, a method of making PGS microparticles through PGSflour remodeling includes mixing PGS flour particles into mineral oil atroom temperature under stirring to evenly disperse the flour particles.The method also includes heating the mineral oil to greater than 50° C.(122° F.) to remodel the thermoplastic fractions of the flour particles.The method further includes applying a vacuum or reduced pressure andheat in the range of 100° C. to 150° C. (212° F. to 302° F.) to theremodeled PGS to crosslink the PGS. After about 24 hours, heating,vacuum, and stirring are removed, and the PGS microparticles arefiltered and washed to remove residual oil.

The various methods described herein for the formation of microparticlesare also amenable to macroparticle development, including macroparticleshaving a diameter up to 3 mm, and even up to about 2 centimeters (cm) indiameter. In macroparticle structures of PGS, the materials may beincorporated into engineering polymers to enhance impact resistance,additive carrier systems, and forms that subsequently act as fusiblefillers into void spaces.

In some embodiments, a method to prepare microcylinders for remodelingincludes a die template to “punch” out cylinders for remodeling or foraddition to a vertical column.

PGS microparticles formed in accordance with exemplary embodiments maybe used for cell technologies and drug delivery applications. In someembodiments, PGS microparticles are loaded with controlled releaseagents, such as, for example, drugs. The PGS microparticles can serve asdrug and cell delivery vehicles, utilizing the innate elastomeric,immunomodulatory, and antimicrobial nature of PGS without additionaladditives. In drug delivery applications, drugs may be add-mixed intothe PGS resin before microparticle formation as a controlled releaseagent, and/or drugs may be loaded onto microparticles after formation,including by surface coating as described.

In some embodiments, the PGS microparticles are coated or loaded withone or more drugs. In some embodiments, the PGS microparticles arecoated with cell adhesion moieties or proteins to improve cell culture.

Distinct lots of microparticles may be synthesized with varying drugloading concentrations or types of drugs. These distinct lots may bemixed or combined in different ratios to deliver various drugs withvarying release kinetics.

In some embodiments, the PGS microparticles are used in a cell deliveryapplication. The microparticles may be used as a cell adhesion substratefor cell delivery. Aggregated microparticles may be used as a porous 3-Dscaffold for cell delivery. Biodegradable PGS microparticles may serveas a temporary substrate for cell attachment, allowing for eventualcell-cell aggregation. This is important as cells behave differently asaggregates (3-D culture) than when adhering to a flat substrate(two-dimensional culture).

In some embodiments, PGS microparticles serve as at least part of adegradable substrate for cell culture, proliferation, differentiation,adhesion, and cluster formation. In some embodiments, PGS microparticlesserve as a cell delivery vehicle. The physicochemical properties of PGSmay be tuned through crosslinking extent or post-treatment to alter thebiocompatibility of the PGS microparticles and tune cell culturecapabilities. In some embodiments, clusters of PGS microparticles,either via PGS scaffolds from microparticles or cell clustering, asshown in FIG. 4, FIG. 10A-10C, FIG. 11, and FIG. 12, for example, areused as a degradable scaffold for tissue formation and cell therapy. Insome embodiments, clusters of PGS microparticles are incorporated into alarger capsule to form a tissue/organ-forming “seed”.

In some embodiments the PGS microparticle can be made in the 3-10 μmrange, which is the size range of red blood cells (RBC). As the PGSmicroparticle is elastic it can mimic the elastic and deformationcharacteristics of RBC's allowing for the ability to pass through thecapillary bed. The ability to create an elastomeric and deformable 3-10μm microparticle also can be used to provide a parenteral, intravenousor cardiovascular drug delivery system that could circulate, and controlrelease a material formulated into the PGS microparticle.

Other medical applications may include in vertebral disc replacement, inspinal spacers for polymers, or in cancer hyperthermia treatment.

For cartilaginous applications such as vertebral disc or meniscal repairor replacement, microparticles derived from rigid plastic-like lactidesand glycolides have the disadvantage of being rigid and exhibitingbulk-eroding degradation kinetics. The rigidity of these materialsresults in compliance mismatch with that of the cartilaginous tissue andthe bulk eroding characteristics results in uncontrolled loss ofmechanical properties and unpredictable release kinetics. PGSmicroparticles are geometrically stable in aqueous environments becauseof the surface erosion feature, resulting in controlled loss ofmechanical properties accompanied by zero order release kinetics.Therefore, a major advantage of this invention is the development of anelastomeric, zero-order release microparticle useful, for instance, injoint spaces and confined tissue structures.

Such a feature and property provide a major advantage for controlledrelease active delivery in applications where joint space disease couldbenefit from a controlled release therapy. For instance, an elastomericmicroparticle formulated with an anti-inflammatory or stem cellcomposition injected into a joint space will likely not cause abrasionor surface damage to epiphyseal surfaces during the therapeutic period.The same would be true for tissues where compression is part of thenormal physiological function such as muscle and tendons.

Furthermore, in compressive joint spaces delivery of a microsphere ormicroparticle through a small-bored delivery device such as a needle orcannula to a specific lesion or targeted site in combination with a PGSbased adhesive such as PGSA or PGSU or PGS/OGS, would provide a methodfor in situ surface remodeling or site-specific therapy.

For cancer hyperthermia treatment, localized heating is used to damageand kill cancer cells at a cancer hyperthermia therapy site, such as,for example, a tumor site. Microparticles or a scaffold ofmicroparticles containing an exogenously-excitable polymeric materialare placed at the tumor site. Exogenous energy then excites theexogenously-excitable polymeric material at the cancer hyperthermiatherapy site to heat the cancer hyperthermia therapy site to ahyperthermia temperature. Appropriate exogenous energy may include, butis not limited to, microwave energy, radiofrequency energy, terahertzenergy, mid-infrared energy, near-infrared energy, visible energy,ultraviolet energy, X-ray energy, magnetic energy, electron beam energy,or a combination thereof. In some embodiments, the exogenously-excitablepolymeric material is PGS. In some embodiments, the microparticles areloaded with one or more chemotherapeutic agents. The biodegradable,biocompatible microspheres degrade over time and therefore do not needto be removed from the cancer hyperthermia therapy site after thetherapy.

Both neat PGS and PGS compounded with spheroids may be used insubterranean exploration as for instance in sealing and gaskettechnologies, such as where a flexible biodegradable gasket may beadvantageous.

Other uses of PGS microparticles may include, but are not limited to, intoys, as a polymer additive for impact resistance, for additivedelivery, for food flavors, or as elastic fillers.

Scaffold Formation

In some embodiments, a 3-D PGS structure or scaffold is formed from PGSmicroparticles. In some embodiments, PGS microparticles are sinteredtogether to form a macro-PGS structure/scaffold. PGS microparticles maybe coated in a PGS resin-based glue to improve sintering, especially ifthe microparticles have limited thermoplastic fractions to remodel. Themicroparticles used in scaffold formation may be sphericalmicroparticles formed in accordance with the embodiments describedherein, irregular shaped microparticles (including PGS flour particles),or a combination thereof.

In some embodiments, variation to the size of the microparticles is usedto tune porosity and pore size of the scaffold. Degradable and/orleachable porogens may be incorporated to further tune porosity and poresize, as well as other fugitive materials. In some embodiments, ascaffold of PGS microparticles includes a microwave dopant, such as, forexample, biodegradable silica.

PGS flour particle size may dictate pore size and shape. The PGS flourmay be remodeled into spheres for microwave sintering/annealing usingphase exclusion liquid or heated gas remodeling to achieve a desiredporosity or pore size. Also, different degrees of polymerization of thePGS flour offer different energy inputs for different microwaveremodeling. In some embodiments, PGS flour is shape-molded into tissuescaffold structures. In some embodiments, PGS flour particle sizevariations include a composition creating a plurality of pore sizes oras a singular particle size to create a narrow pore size distribution.

In some embodiments, spherical PGS particles establish a cell scaffoldtemplate. For example, aggregates of PGS microparticles may be formed tocreate porous 3-D structures, as shown schematically in FIG. 8. Whiledescribed primarily with respect to spheres, the particle shape is notso limited and may include other geometric forms resulting from theprocess configuration and set-up.

Different distinct lots of microparticles (e.g. different sizes and/orcomposition) may also be combined to form scaffolds as seen in FIG. 8.The scaffolds are then able to release a multitude of drugs withouthaving to incorporate every drug into each microparticle. Inregenerative medicine applications, patterned or ordered complex tissuegrowth may be dictated by combining distinct lots of microparticles inseparate regions. Distinct lots of microparticles may also be combinedto form a gradient or gradients of drugs in a scaffold. Similarly,distinct lots of microparticles may be used to culture different celltypes. A patterned or gradient configuration of these microparticle-cellconjugates may then be constructed in a scaffold to derive complextissue/organ formation.

Selection of a plurality or specified selection of PGS thermosetmicronized particles may be made to modulate porosity and topology undervarious radiant energy processes.

In some embodiments, a method of forming a scaffold incorporates theconcept of “lost-wax” or cire perdue so that the organ-scaffold shapeincluding unusual anatomical topology is held together with a fugitivebinder, such as polyvinyl alcohol or paraffin, that is removed followingthe microwave sintering/annealing of the PGS flour particles.

A scaffold having a spherical shape 90 is shown in FIG. 10A; thescaffold is formed from PGS flour in a shell 92 around a hollow core 94,as shown in FIG. 10B and FIG. 10C.

In some embodiments, a method of making a PGS scaffold frommicroparticles includes combining and shaping PGS microparticles, eitheras a free-standing structure or packed into a mold. The method alsoincludes sintering/annealing and curing the microparticles via high heatand vacuum or via microwaves to produce a scaffold of PGS with pores, asshown in the image of FIG. 11 of PGS flour after sintering/annealing andcuring, which is a magnified view showing the microstructure of thescaffold of FIG. 10A.

The pore-scaffold porosity may be dictated by PGS flour particle size orinclusion of fugitive materials that can be removed either duringmicrowaving or as a separate process.

The raw flour may be modified to affect the properties of the resultingscaffold. The particle size distribution of the PGS flour modulates theporosity. Such modifications may include, but are not limited to,geometric shape variations, providing nutritional doping or bioactiveagents to the particle, providing API or biologic agents, providing genetransfer technology agents, providing co-polymer development particledevelopment agents, or providing island agents in the sea matrixdissolution.

The microwave process may also be modified to affect the properties ofthe resulting scaffold. Such modifications may include, but are notlimited to, selective shapes and molds, selective energy processing withmicrowave dopants, pre-conditioning of flour-to-sphere phase exclusionremodeling, or pre-loading of cells.

In some embodiments, spherical PGS microparticles and/or irregularlyshaped PGS flour particles serve as a base for a scaffold in the form ofa mini-implantable bioreactor. In some embodiments, the PGSmicroparticles are microwave-annealed into a capsular shape having ahollow center and a modulated wall porosity. The particle size,sintering/annealing energy, and sintering/annealing time are selected tomodulate the pore size through the capsule wall. The hollow center ofthe capsule is a “cell bed” for cell media and cells to expand in situ.The microparticles may be fortified with nutrients and/or oxygenationentities. A supporting capsular periphery may be further “hardened” bythermal methods to provide an implantable capsule. The capsule size maybe selected based on the requirements for the implant.

A mini-implantable bioreactor 100 formed from PGS particles may bespherical or egg-shaped (ovoid), as shown schematically in FIG. 12. ThePGS microparticles 102, which may be PGS flour microparticles, form anouter shell defining the general shape of the mini-implantablebioreactor 100 with interstitial space and porosity 104 between PGSmicroparticles 102. The hollow capsular core 106 defined by the PGSmicroparticle 102 shell holds cells 108 in a cell culture. Themini-implantable bioreactor 100 may further include an extra-peripheralsupport film or annealing “skin” 110. This annealing skin 110 may bepost-processed by laser ablation to provide through-holes in theannealing skin 110. The mini bioreactor 100 may be a transfer capsule ofexpanded cells 108 for cell therapy based on PGS microparticletechnologies.

In some embodiments, PGS flour particles are processed into a film froma powder. Target objects may be PGS-coated similar to powder coating,such as a microwave PGS flour powder coating. In some embodiments, asubstrate is powder-coated with flour particles. In some embodiments, a3-D scaffold is designed for an entire organ system as a mold filler oras a composition containing flour that is exposed to microwave energyfollowing shaping. In some embodiments, a method of “lost-wax” or cireperdue forms the organ-scaffold shape, including an unusual anatomicaltopology, with the shape being held together with a fugitive binder,such as, for example, polyvinyl alcohol or paraffin, that is removedfollowing the microwave sintering/annealing of the PGS flour particles.

EXAMPLES

The invention is further described in the context of the followingexamples which are presented by way of illustration, not of limitation.

Example 1

200 mL of heavy mineral oil was heated to 130° C. (266° F.) in a reactorvessel under stirring with a magnetic stir bar (400 RPM), and a vacuum(10 torr) was applied to the mineral oil to remove dissolved gases. Thevacuum was removed and 2 mL of molten PGS was slowly added directly tothe hot mineral oil under stirring through a syringe with an 18-gauge(18 G) needle. After the PGS resin was added, the 10-torr vacuum wasreapplied and the PGS microparticles were maintained at 130° C. (266°F.) and under stirring to cure the PGS. After 20 hours, the heat,vacuum, and stirring were removed. The cured PGS microparticles werethen washed and collected. FIG. 1 shows microparticles 10 and 20 formedby Example 1 using different shear rates resulting from different sizedstir bars (lower shear rates result in larger sized microparticles).

Example 2

200 g of heavy mineral oil was mixed with 6 g of monolaurin and heatedto 130° C. (266° F.) in a reactor vessel under stirring with a magneticstir bar (400 RPM), and a vacuum (10 torr) was applied to the mineraloil and monolaurin mixture to remove dissolved gases. The vacuum wasremoved and 1 mL of molten PGS was slowly added to the hot mineral oilunder stirring through a syringe with an 18 G needle. After the PGSresin was added, the 10-torr vacuum was reapplied and the PGSmicroparticles were maintained at 130° C. (266° F.) and under stirringto cure the PGS. After 20 hours, the heat, vacuum, and stirring wereremoved. The cured PGS microparticles were then washed and collected.FIG. 2 shows the microparticles 10 formed by Example 2.

Example 3

PGS microspheres were formed by emulsion with alginate as an emulsifyingagent. PGS resin at 50 wt % solubilized in 99% isopropyl alcohol wasadded dropwise to an aqueous solution of 1 wt % alginate with stirringof the alginate solution at the time of addition to form uncured PGSmicrospheres. The PGS-microsphere-containing alginate solution was addeddropwise to a 90 millimolar (mM) CaCl₂ solution to rapidly ionically gelthe alginate into spheres containing the uncured PGS microspheres. Thealginate spheres were washed multiple times with deionized water toremove the excess calcium chloride. The deionized water was thenremoved, leaving hydrated PGS-alginate spheres.

The hydrated PGS-alginate spheres were then frozen. The frozenPGS-alginate spheres were then lyophilized to remove the water. The dryPGS-alginate spheres were then microwave-cured for two minutes at anintermediate power in an inverter microwave oven to crosslink the PGSmicrospheres, thereby forming cured, alginate-entrapped PGSmicrospheres. The cured, alginate-entrapped PGS microspheres were thenplaced into a 135 mM sodium citrate solution that was stirred at 400 RPMfor one hour to chelate the divalent cations away from the alginate.This reverses the alginate crosslinking and causing the alginate todegrade, releasing the cured PGS microparticles from the alginate. Thecured PGS microparticles were then concentrated by centrifugation andwashed multiple times with deionized water to remove residual degradedalginate and sodium citrate salts prior to drying and storage of thefinal PGS microparticles.

FIG. 7 shows an image of final PGS microparticles post-cure in deionizedwater, as prepared by the PGS-alginate synthesis process of Example 3.The PGS microparticles have an average size of 79.3 μm, covering a rangefrom 14.3 μm to 169.3 μm.

Example 4

PSA formulation hand sheets were prepared using poly (glycerol-sebacate)(PGS) resin formulated with a commercially available polyisobutylene(PIB) resin. PSA formulations were prepared withelastomer(PIB):ester(PGS) ratios of 25:75 w/w, 50:50 w/w, and 75:25 w/w.

The PSA formulations were imaged by an LDIR microscope (AgilentTechnologies, Santa Clara, Calif.), a commercially available imagingmicroscope (PerkinElmer, Inc., Waltham, Mass.), and an FT-IRspectrometer commercially available under the Stingray trade name(DigiLab, Inc., Hopkinton, Mass.).

FIG. 9A, FIG. 9B, and FIG. 9C show the resulting LDIR images for the25:75 w/w, 50:50 w/w, and 75:25 w/w elastomer:ester ratio PSAformulations, respectively. The light represents the PGS, whereas thedark represents the PIB. The LDIR images show the phase inversion inboth the 25:75 and 75:25 samples. Only the 50:50 PSA formulation showedan aggregate of both components at the surface. The 50:50 PSAformulation had the highest tack of the three formulations.

Example 5

A sample of a commercially available proprietary acrylic PSA wound careadhesive was formulated with PGS to form a releasable PSA formulation.

The release of the PSA adhesion from the skin for this releasable PSAformulation is facilitated by the design of the PSA carrier film.Laser-drilled micropore through-holes in the PSA carrier film provide anopen vertical conduit to the bulk adhesive from the dressing top-side.To remove the PSA, IPA is swabbed over the perforated carrier. The IPAthen wicks down through the micropore holes to penetrate the bulk film.

Example 6

Flour particles were made from PGS thermosets that were cured for 24hours in a vacuum oven (120° C., 10 torr). The thermosets weresnap-frozen with liquid nitrogen and crushed into small pieces less than1 cm in size. The pieces were then cryoground into fine particles lessthan 500 μm in diameter. To sinter flour particles together, the flourparticles were packed in close proximity and microwaved to enableremodeling of the particles.

To create porous, 3-dimensional structures from flour particles, theparticles were packed around a ceramic bead. The particles and ceramicbead were then microwaved to sinter the flour particles together. Theceramic bead was removed, and the sintered particles were then furthercrosslinked in a vacuum oven (120° C., 10 torr) for 15 hours to create atack-free scaffold, as shown in FIG. 10A, FIG. 10B, and FIG. 10C.

Example 7

A variation of the process described in Example 3 was prepared in whichthe addition of 1 wt % curcumin agent for release is captured in moltenneat PGS resin that is subsequently formed into microspheres usingalginate as an emulsifying agent. FIG. 13 shows FTIR spectraestablishing that curcumin is present in PGS microspheres followingextraction from alginate and subsequent washing steps due to aromaticC═C peak near 1500 cm⁻¹ only being present in curcumin molecularstructure. PGS microspheres following washing are shown in FIG. 14;observation demonstrated an exhibited yellow coloration confirming theloading of curcumin that was not seen in the PGS microspheres formedwithout the addition of that agent.

All above-mentioned references are hereby incorporated by referenceherein.

While the invention has been described with reference to one or moreembodiments, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings of the invention without departing from theessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment disclosed as the best modecontemplated for carrying out this invention, but that the inventionwill include all embodiments falling within the scope of the appendedclaims. In addition, all numerical values identified in the detaileddescription shall be interpreted as though the precise and approximatevalues are both expressly identified.

What is claimed is:
 1. A method of forming a pressure-sensitive adhesivecomprising: combining an uncured polymeric ester resin and at least onecontrolled release agent to form an ester phase of the uncured polymericester resin loaded with the at least one controlled release agent; andcombining the ester phase comprising the uncured polymeric ester resinand the at least one controlled release agent with an elastomer phasecomprising an elastomeric polymer resin, at a ratio of esterphase:elastomer phase selected to provide the ester phase as a disperseddiscontinuous microspherical phase in a continuous matrix of theelastomer phase, to form a pressure-sensitive adhesive composition.
 2. Amethod of forming a plurality of cured microparticles comprising:providing a composition comprising a poly(glycerol sebacate) resin in anuncured state; and forming the composition into a plurality of uncuredmicroparticles, the plurality of uncured microparticles being free of aphoto-induced crosslinker, and curing the plurality of uncuredmicroparticles to form the plurality of cured microparticles; whereinthe forming comprises combining the composition with aphase-incompatible liquid and suspending the plurality of uncuredmicroparticles in a matrix of the phase-incompatible liquid; and whereinthe phase-incompatible liquid is an elastomer.
 3. The method of claim 2,wherein the curing comprises applying microwave radiation to theplurality of uncured microparticles.
 4. The method of claim 2 furthercomprising loading the poly(glycerol sebacate) resin with at least onecontrolled release agent.
 5. The method of claim 2, wherein theplurality of uncured microparticles consists of the poly(glycerolsebacate) resin.
 6. The method of claim 2, wherein the poly(glycerolsebacate) resin comprises a poly(glycerol sebacate acrylate) resin. 7.The method of claim 2, wherein the poly(glycerol sebacate) resincomprises a poly(glycerol sebacate urethane) resin.
 8. The method ofclaim 1, wherein the uncured polymeric ester resin is uncuredpoly(glycerol sebacate) resin.
 9. The method of claim 2, wherein thecuring comprises conductively heating the plurality of uncuredmicroparticles.
 10. The method of claim 2, wherein the elastomer isacrylic-based or isobutylene-based.